Effects of Storage Method on Intestinal Allograft Immune Profile and Viability
Abstract
Intestinal failure can be caused by a variety of clinical conditions including trauma-related small bowel injury, bacterial infection, and inflammatory bowel disease, all of which can lead to the loss of intestinal function. Military Service members, especially those in combat roles, are at an increased risk for severe abdominal injuries when compared to the civilian population. Improvised explosive devices (IEDs) can cause devastating abdominal injuries including loss of small bowel (SB) function. Current treatment options for patients with intestinal failure include intravenous (or “parenteral”) nutrition. However, this method is associated with numerous complications, including high risks of infection, vascular access difficulties, and overall poor quality of life. Intestinal transplantation (IT) is a viable alternative treatment strategy for patients who suffer from severe intestinal dysfunction and SB failure. However, there has been limited progress made over the last decade in the improvement of both organ and patient survival following IT. Additionally, the effects and clinical potential of more recent advances in organ preservation strategies for more common solid organ transplants, such as the liver, remain unknown for IT. There is critical need to address these gaps in knowledge for SB transplants, which will improve patient outcomes and advance the practice of IT. A promising organ preservation strategy for large organ transplants that has recently emerged is normothermic machine perfusion (NMP). NMP involves the use of a machine that continuously perfuses the organ awaiting transplant with oxygenated blood and replicates the organ’s normal physiological environment. The use of NMP for organ transplantation has several benefits compared to standard, cold storage organ preservation. NMP is thought to prevent organ injury caused by lack of oxygen in the time between organ procurement and transplantation that is common in cold storage preservation, and NMP allows the ability to manipulate the perfusate in order to mobilize and filter populations of immune cells or infuse protective medications or populations of cells. However, despite the known advantages of NMP over traditional cold storage for organ transplants, its use in SB transplants has been largely unexplored. Moreover, even basic information about the effect of NMP on SB viability and innate immune response to the storage method remain unknown. This proposal addresses the Fiscal Year 2018 Peer Reviewed Medical Research Program topic area: Immunomonitoring of Intestinal Transplants. We will address the gap in knowledge regarding optimal preservation methods for SB transplants by comparing the effects of NMP using oxygenated blood versus standard cold storage on the transplant organ’s immune profile (emphasis on intestine-resident immune cells, including intraepithelial lymphocytes), microbial communities, and stem cell viability. Initial measurements will utilize excess intestine from human donors. To understand the effects of preservation on acute immune-remodeling events in the intestine post-transplant, and overall transplant survival, we will use the well-accepted porcine (pig) IT model. The pig model will provide new insight into intestinal tissue dynamics during the first 7 days post-transplant, a window of time where studies in humans are not possible. We will use excess SB from human donors to determine changes in the immune profile and microbiota that are attributable to NMP. Next, we will use our porcine model of IT to determine the relationship between the pre-transplant immune profile with host immune response after cold storage vs. NMP. Using 3D human culture models, we will then compare stem cell viability from SB segments after different preservation conditions. We will then sample SB transplants to measure stem cell viability over time in the first week post-transplant comparing cold storage vs. NMP in our porcine IT
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910676
Entities
People
- Debra L. Sudan
Organizations
- Duke University
- United States Army